Corticotropin releasing hormone promotes inflammatory bowel disease via inducing intestinal macrophage autophagy

Psychosocial stress is a vital factor contributing to the pathogenesis and progression of inflammatory bowel disease (IBD). The contribution of intestinal macrophage autophagy to the onset and development of IBD has been widely studied. Herein, we investigated the underlying mechanism of psychosocial stress in an IBD mouse model pertaining to macrophage autophagy. Corticotropin releasing hormone (CRH) was peripherally administrated to induce psychosocial stress. For in vivo studies, dextran sulfate sodium (DSS) was used for the creation of our IBD mouse model. For in vitro studies, lipopolysaccharide (LPS) was applied on murine bone marrow-derived macrophages (BMDMs) as a cellular IBD-related challenge. Chloroquine was applied to inhibit autophagy. We found that CRH aggravated the severity of DSS-induced IBD, increasing overall and local inflammatory reactions and infiltration. The levels of autophagy in intestinal macrophages and murine BMDMs were increased under these IBD-related inflammatory challenges and CRH further enhanced these effects. Subsequent administration of chloroquine markedly attenuated the detrimental effects of CRH on IBD severity and inflammatory reactions via inhibition of autophagy. These findings illustrate the effects of peripheral administration of CRH on DSS-induced IBD via the enhancement of intestinal macrophage autophagy, thus providing a novel understanding as well as therapeutic target for the treatment of IBD.

Intestinal Macrophage Autophagy and its Pharmacological Application in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), comprised of Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory disorders. IBD is regarded as a severe healthcare problem worldwide, with high morbidity and lethality. So far, despite of numerous studies on this issue, the specific mechanisms of IBD still remain unclarified and ideal treatments are not available for IBD. The intestinal mucosal barrier is vital for maintaining the function of the intestinal self-defensive system. Among all of the components, macrophage is an important one in the intestinal self-defensive system, normally protecting the gut against exotic invasion. However, the over-activation of macrophages in pathological conditions leads to the overwhelming induction of intestinal inflammatory and immune reaction, thus damaging the intestinal functions. Autophagy is an important catabolic mechanism. It has been proven to participate the regulation of various kinds of inflammation- and immune-related disorders via the regulation of inflammation in related cells. Here in this paper, we will review the role and mechanism of intestinal macrophage autophagy in IBD. In addition, several well-studied kinds of agents taking advantage of intestinal macrophage autophagy for the treatment of IBD will also be discussed. We aim to bring novel insights in the development of therapeutic strategies against IBD.

The Gut–Liver Axis in Chronic Liver Disease: A Macrophage Perspective

Chronic liver disease (CLD) is a growing health concern which accounts for two million deaths per year. Obesity, alcohol overconsumption, and progressive cholestasis are commonly characterized by persistent low-grade inflammation and advancing fibrosis, which form the basis for development of end-stage liver disease complications, including hepatocellular carcinoma. CLD pathophysiology extends to the intestinal tract and is characterized by intestinal dysbiosis, bile acid dysregulation, and gut barrier disruption. In addition, macrophages are key players in CLD progression and intestinal barrier breakdown. Emerging studies are unveiling macrophage heterogeneity and driving factors of their plasticity in health and disease. To date, in-depth investigation of how gut–liver axis disruption impacts the hepatic and intestinal macrophage pool in CLD pathogenesis is scarce. In this review, we give an overview of the role of intestinal and hepatic macrophages in homeostasis and gut–liver axis disruption in progressive stages of CLD.

The mannose receptor (CD206) identifies a population of colonic macrophages in health and inflammatory bowel disease

To understand the contribution of mononuclear phagocytes (MNP), which include monocyte-derived intestinal macrophages, to the pathogenesis of inflammatory bowel disease (IBD), it is necessary to identify functionally-different MNP populations. We aimed to characterise intestinal macrophage populations in patients with IBD. We developed 12-parameter flow cytometry protocols to identify and human intestinal MNPs. We used these protocols to purify and characterize colonic macrophages from colonic tissue from patients with Crohn’s disease (CD), ulcerative colitis (UC), or non-inflamed controls, in a cross-sectional study. We identify macrophage populations (CD45+CD64+ HLA-DR+) and describe two distinct subsets, differentiated by their expression of the mannose receptor, CD206. CD206+ macrophages expressed markers consistent with a mature phenotype: high levels of CD68 and CD163, higher transcription of IL-10 and lower expression of TREM1. CD206− macrophages appear to be less mature, with features more similar to their monocytic precursors. We identified and purified macrophage populations from human colon. These appear to be derived from a monocytic precursor with high CCR2 and low CD206 expression. As these cells mature, they acquire expression of IL-10, CD206, CD63, and CD168. Targeting the newly recruited monocyte-derived cells may represent a fruitful avenue to ameliorate chronic inflammation in IBD.

Beyond Immunity: Underappreciated Functions of Intestinal Macrophages

The gastrointestinal tract hosts the largest compartment of macrophages in the body, where they serve as mediators of host defense and immunity. Seeded in the complex tissue-environment of the gut, an array of both hematopoietic and non-hematopoietic cells forms their immediate neighborhood. Emerging data demonstrate that the functional diversity of intestinal macrophages reaches beyond classical immunity and includes underappreciated non-immune functions. In this review, we discuss recent advances in research on intestinal macrophage heterogeneity, with a particular focus on how non-immune functions of macrophages impact tissue homeostasis and function. We delve into the strategic localization of distinct gut macrophage populations, describe the potential factors that regulate their identity and functional heterogeneity within these locations, and provide open questions that we hope will inspire research dedicated to elucidating a holistic view on macrophage-tissue cell interactions in the body’s largest mucosal organ.

E prostanoid receptor 4 expressing macrophages promote the regeneration of the intestinal epithelial barrier upon inflammation

Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of resolution of inflammation but the mechanisms underlying their mucosal healing capacity remains elusive. Here, we describe a subset of E prostanoid receptor 4 (EP4) expressing intestinal macrophages with mucosal healing properties both in human and mice. Notably, Csf1r-iCre EP4-fl/fl mice showed defective mucosal healing and intestinal epithelial barrier regeneration in a dextran sodium sulfate-induced colitis model. Mechanistically, an increased mucosal level of prostaglandin E2 (PGE2) triggers the secretion of chemokine (C-X-C motif) ligand 1 (CXCL1) in monocyte-derived EP4+ macrophages via MAPKs. Subsequently, CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during the resolution phase of colitis. Thus, EP4+ intestinal macrophages are essential for the support of the intestinal stem cell niche and for the regeneration of the injured epithelium.One Sentence SummaryProstaglandin E2 licenses E-type prostanoid receptor 4 intestinal macrophage regenerative capacity promoting mucosal healing via the secretion of CXCL1

Endothelial basement membrane laminins as an environmental cue in monocyte differentiation to macrophages

Monocyte differentiation to macrophages is triggered by migration across the endothelial barrier, which is constituted by both endothelial cells and their underlying basement membrane. We address here the role of the endothelial basement membrane laminins (laminins 411 and 511) in this monocyte to macrophage switch. Chimeric mice carrying CX3CR1-GFP bone marrow were employed to track CCL2-induced monocyte extravasation in a cremaster muscle model using intravital microscopy, revealing faster extravasation in mice lacking endothelial laminin 511 (Tek-cre::Lama5-/-) and slower extravasation in mice lacking laminin 411 (Lama4-/-). CX3CR1-GFPlow extravasating monocytes were found to have a higher motility at laminin 511 low sites and to preferentially exist vessels at these sites. However, in vitro experiments reveal that this is not due to effects of laminin 511 on monocyte migration mode nor on the tightness of the endothelial barrier. Rather, using an intestinal macrophage replenishment model and in vitro differentiation studies we demonstrate that laminin 511 together with the attached endothelium collectively promote monocyte differentiation to macrophages. Macrophage differentiation is associated with a change in integrin profile, permitting differentiating macrophages to distinguish between laminin 511 high and low areas and to migrate preferentially across laminin 511 low sites. These studies highlight the endothelial basement membrane as a critical site for monocyte differentiation to macrophages, which may be relevant to the differentiation of other cells at vascular niches.

Gut-resident CX3CR1hi macrophages induce tertiary lymphoid structures and IgA response in situ

Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2+CX3CR1lo, Ccr7+CX3CR1int (lymph migratory), and Cxcl13+CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13+CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7+CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.